Article ; Online: Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression.
2022 Volume 14, Issue 6
Abstract: Screening of a protein kinase inhibitor library identified SB431542, targeting activin receptor-like kinase 5 (ALK5), as a compound interfering with SARS-CoV-2 replication. Since ALK5 is implicated in transforming growth factor β (TGF-β) signaling and ... ...
| Abstract | Screening of a protein kinase inhibitor library identified SB431542, targeting activin receptor-like kinase 5 (ALK5), as a compound interfering with SARS-CoV-2 replication. Since ALK5 is implicated in transforming growth factor β (TGF-β) signaling and regulation of the cellular endoprotease furin, we pursued this research to clarify the role of this protein kinase for SARS-CoV-2 infection. We show that TGF-β1 induces the expression of furin in a broad spectrum of cells including Huh-7 and Calu-3 that are permissive for SARS-CoV-2. The inhibition of ALK5 by incubation with SB431542 revealed a dose-dependent downregulation of both basal and TGF-β1 induced furin expression. Furthermore, we demonstrate that the ALK5 inhibitors SB431542 and Vactosertib negatively affect the proteolytic processing of the SARS-CoV-2 Spike protein and significantly reduce spike-mediated cell-cell fusion. This correlated with an inhibitory effect of ALK5 inhibition on the production of infectious SARS-CoV-2. Altogether, our study shows that interference with ALK5 signaling attenuates SARS-CoV-2 infectivity and cell-cell spread via downregulation of furin which is most pronounced upon TGF-β stimulation. Since a TGF-β dominated cytokine storm is a hallmark of severe COVID-19, ALK5 inhibitors undergoing clinical trials might represent a potential therapy option for COVID-19. |
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| MeSH term(s) | COVID-19 ; Cell Fusion ; Furin ; Humans ; Protein Serine-Threonine Kinases ; Receptor, Transforming Growth Factor-beta Type I ; Receptors, Transforming Growth Factor beta/metabolism ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta1/metabolism |
| Chemical Substances | Receptors, Transforming Growth Factor beta ; Spike Glycoprotein, Coronavirus ; Transforming Growth Factor beta ; Transforming Growth Factor beta1 ; spike protein, SARS-CoV-2 ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Receptor, Transforming Growth Factor-beta Type I (EC 2.7.11.30) ; Furin (EC 3.4.21.75) |
| Language | English |
| Publishing date | 2022-06-15 |
| Publishing country | Switzerland |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2516098-9 |
| ISSN | 1999-4915 ; 1999-4915 |
| ISSN (online) | 1999-4915 |
| ISSN | 1999-4915 |
| DOI | 10.3390/v14061308 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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